14-39154255-T-G

Variant names:

• chr14-39154255-T-G
• rs2139378563
• NM_001079537.2:c.307A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001079537.2(TRAPPC6B):​c.307A>C​(p.Thr103Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T103I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRAPPC6B NM_001079537.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59
• Publications: 0 publications found

Genes affected

TRAPPC6B (HGNC:23066): (trafficking protein particle complex subunit 6B) TRAPPC6B is a component of TRAPP complexes, which are tethering complexes involved in vesicle transport (Kummel et al., 2005 [PubMed 16025134]).[supplied by OMIM, Mar 2008]

TRAPPC6B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079537.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC6B	NM_001079537.2	MANE Select	c.307A>C	p.Thr103Pro	missense	Exon 4 of 6	NP_001073005.1	Q86SZ2-1
	TRAPPC6B	NM_177452.4		c.268-2416A>C		intron	N/A	NP_803235.1	Q86SZ2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC6B	ENST00000330149.10	TSL:1 MANE Select	c.307A>C	p.Thr103Pro	missense	Exon 4 of 6	ENSP00000330289.5	Q86SZ2-1
	TRAPPC6B	ENST00000347691.9	TSL:1	c.268-2416A>C		intron	N/A	ENSP00000335171.6	Q86SZ2-2
	TRAPPC6B	ENST00000555269.5	TSL:1	n.*187A>C		non_coding_transcript_exon	Exon 4 of 6	ENSP00000452236.1	G3V4C3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.29
Sift	Benign	0.090	T
Sift4G	Benign	0.10	T
Polyphen		0.40	B
Vest4		0.63
MutPred		0.49		Gain of catalytic residue at A107 (P = 0.0038)
MVP		0.63
MPC		0.48
ClinPred		0.94	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.60
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2139378563; hg19: chr14-39623459;